Mass spectrometry imaging (MSI) is an emerging tool for mapping the spatial distribution of analytes in biological tissues at the molecular level. MSI has been successfully utilized to obtain rapid 2-D or 3-D spatial distributions of biological species (e.g., lipids, drugs and metabolites) present on different tissue slices (e.g., kidney, brain, liver, and tumor). This emerging scientific technology has the potential to reshape the analytical science of many research disciplines including human medicine, e.g., drug delivery and metabolomics, target cancer therapy, and cancer diagnosis.
A pivotal focus of MSI technique development is the improvement of the spatial resolution, and an ultimate goal in detection resolution is the ability to sample a single cell with mass spectrometry (MS). The ability to interrogate the molecular constituents of individual cells will be a major advancement in biological science. Currently and classically, molecular cell component analysis is almost exclusively done through lysate preparation of a cell population or a tissue sample, and all analysis represents an average of the disparate characteristics of the individual cells present; this limitation applies to common experimental analysis methods such as Western blotting and lipid analysis. Additionally, the preparation of a lysate or an extract from such a heterogeneous sample creates a completely ex vivo biological context—extremely disruptive reagents or processes rip apart the rigorous-spatially segregated cell, mixing all the constituents into a completely artificial milieu. This less-than-ideal experimental approach has been necessary due to the lack of analytical sampling sensitivity, and it is currently impossible to know how this deficient sample preparation system might have produced incorrect or biased results in countless experiments over the modern history of biological science. Single cell MS has the potential to completely change the paradigm of biological sampling for molecular analysis, and the impact of this technical advancement is impossible to underestimate.
Depending on the ionization environment, MSI can be generally classified into two major categories: (a) MSI under vacuum, such as secondary ion mass spectrometry (SIMS) and matrix-assisted laser desorption ionization (MALDI), and (b) ambient pressure MSI, such as desorption electrospray ionization (DESI), laser ablation electrospray ionization mass spectrometry (LAESI), and nanospray desorption electrospray ionization (nano-DESI). Although all above techniques, except for nano-DESI, have been commercialized, their applications are still limited by their drawbacks. Due to the difficulties to obtained high vacuum for samples containing water, the application of SIMS to biological systems has been greatly limited. In spite that MALDI has become the major technique for MIS, surface treatment is obligatory and very time-consuming. In addition, there are concerns regarding the influence of sample preparation on the spatial distribution of analytes. The development of ambient desorption/ionization techniques allows rapid imaging measurement without (or very little, if any) treatment of surfaces. However, these MSI techniques, including DESI, LAESI, and nano-DESI, have their own inherent shortcomings. For example, DESI has relatively low spatial resolution as well as issues of sensitivity, ionization efficiency, and tissue-specific ion suppression effects. LAESI is a destructive method, such that experiments are nearly non-reproducible. Nano-DESI is non-destructive and provides a high resolution, whereas the fabrication of the imaging probes and the operation of the device are challenging. Therefore, the development of new methods to improve existing MSI technique is urgently needed.